As the beginning of the 21st century, over 65% of the U.S. adult population is overweight or obese, and obesity has now become one of the top three causes of death in the United States. The neural circuits affected by drugs of abuse and presumably altered in the addicted individual are the very pathways that control intake of our most vital natural reward, food. The neural system most clearly implicated in the rewarding actions of both drugs of abuse and food is the ventral striatum and its associated corticostriatal circuitry. In order to understand and successfully treat the diseases of addiction and obesity, it is necessary to determine the exact neurochemical nature of their underlying mechanisms. The research proposed here will investigate the central interactions of the cannabionid and opioid systems within an established model of hedonically-driven binge eating of palatable food. Evidence from both animal and human studies have demonstrated that selectively activating or inactivating either the endocannabinoid or opioid system can produce powerful influences on appetite and feeding behavior. However, very little is known regarding the neural structures and pathways that mediate this unique interaction of opioids and cannabinoids that lead to robust alterations in feeding behavior. The present proposal aims to address these questions by administering a cannabinoid receptor antagonist into three corticostriatal structures (nucleus accumbens, basolateral and central nucleus of the amygdala) with or without concurrent opioid activation of the nucleus accumbens followed by three hours of automated recording of a variety of feeding behaviors. Intra-accumbens opioid activation is a well characterized model of hedonically-driven binge eating and has been shown to depend on activation of the amygdala. Overconsumption of a diet high in sugar and fat, much like the sweetened high-fat diet currently proposed, has been shown to precede obesity in the majority of cases. The cannabinoid and opioid systems and their yet undefined neural sites of action are likely to be critical mediators of this behavior. The goal of the proposed research is to further our understanding of the neural pathways that mediate the relationship between endocannabinoid and opioid systems and how they influence hedonically-driven feeding. These studies are critical to understanding the mechanisms underlying a current epidemic that threatens our public health and yet is poorly understood. In order to understand and successfully treat the disease of addiction and obesity, it is necessary to determine the exact neurochemical nature of their underlying mechanisms. The goal of this project is to further the understanding of neural pathways that mediate the relationship between endocannobinoid and opioid systems and how the influence hedonically-driven feeding. These studies are critical to understanding the mechanisms underlying a current epidemic that threatens our public health and yet is poorly understood.